Bis-carbamylguanidinoazaalkane antimicrobial compounds

ABSTRACT

Antimicrobial compounds are disclosed having the formula:

REFERENCE TO RELATED APPLICATION

This application is a continuation in-part of Applicant's copendingapplication Ser. No. 627,139, filed Oct. 30, 1975, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to novel compounds which are useful as topicalantimicrobial agents and more particularly to antimicrobial compoundswhich are effective against the microorganisms that produce dentalplaque, which have a prolonged intraoral residence time andantimicrobial activity, which have an acceptable taste, and which do notstain the teeth or gums.

Dental plaque is a soft, tenacious bacterial deposit which forms on thesurface of the teeth. It is produced by the action of certain bacteriaviz., S.mutans, A.viscosus, and A.naeslundi, on carbohydrate substancesin the mouth. Of the numerous antimicrobial agents that have beeninvestigated for their ability to inhibit plaque formation, only1,6-bis-(p-chlorophenylbiguanidino)hexane (chlorhexidine) and1,6-bis-(2-ethylhexylbiguanidino)hexane (alexidine) are reported to beclinically effective antiplaque agents. However, because these agentsare extremely strong organic bases, and consequently are almost entirelycationic at the prevailing pH of the mouth, they suffer from thefollowing disadvantages: (1) they are extremely bitter-tastingsubstances with a prolonged bitter after-taste lasting up to severalhours, (2) they alter taste perception of foodstuffs for several hours,(3) with prolonged use they produce stains of various colors on theteeth, tongue, gums, oral mucosa, (4) they produce local irritation ofthe oral mucosa and tongue.

A class of carbamylguanidine topical antimicrobial compounds whichavoids some of the deficiencies of the prior art compounds is disclosedin U.S. Pat. application Ser. No. 546,549. This application disclosesfurther carbamylguanidine antimicrobial compounds having improvedproperties with respect to both the bis-biguanide antimicrobials and thecompounds of U.S. Ser. No. 546,549, now U.S. Pat. No. 4,022,962.

SUMMARY OF THE INVENTION

It is accordingly the objective of this invention to provide novelcompounds which are useful as topical, non-systemic antimicrobialagents. A further objective is to provide novel antimicrobial compoundswhich can reversibly adsorb to teeth and oral mucosa and which areprolonged-acting inhibitors of plaque producing bacteria, which arerelatively safe to mammals by oral administration, which have anacceptable taste and do not alter taste perception, and which do notstain teeth, gums, tongue, or oral mucosa.

It has now been found that the objectives of this invention can beattained by providing antimicrobial compounds related to thebis-biguanides, but in which the strongly basic biguanide functions havebeen replaced by the weaker basic functions carbamylguanidino, orthiocarbamylguanidino. The objectives of this invention have beenattained by using novel compounds of the formula:

    Z-B-Y-B-Z . rHA

wherein B is carbamylguanidino or thiocarbamylguanidino, Y is anitrogen-containing alkylene group having the structural formula##STR2## wherein: n = 2-4

m = 2-4

p = 1,2

q = 2-4

x = 0-3

y = 0-2

and x = 0 when y ≠ 0 and y = 0 when x ≠ 0, and R is hydrogen or a C₁ -C₈hydrocarbon radical selected from the group consisting of alkyl,alkenyl, alkynyl, cycloalkyl and aralkyl radicals, and R' and R" areeach hydrogen or C₁ -C₄ alkyl and may be the same or different, and Z isselected from the group consisting of C₁ -C₁₂ alkyl; di(C₁ -C₁₀alkylamino)-C₁₀ -C₂ alkyl having a total carbon content of C₄ -C₁₂ ; C₃-C₁₂ alkenyl; C₃ -C₁₂ alkynyl; C₃ -C₁₂ cycloalkyl; C₄ -C₁₂cycloalkylalkyl; C₆ -C₁₂ cycloalkenyl; C₇ -C₁₄ cycloalkenylalkyl; C₇-C₁₂ polycycloalkyl; C₈ -C₁₄ polycycloalkylalkyl; C₈ -C₁₂polycycloalkenyl; C₈ -C₁₄ polycycloalkenylalkyl; C₁ -C₁₀ alkoxy-C₁₀ -C₂alkyl having a total carbon content of C₃ -C₁₄ ; C₁ -C₁₀ alkylthio-C₁₀-C₂ alkyl having a total carbon content of C₃ -C₁₄ ; phenoxy C₂ -C₆alkyl; phenylthio C₂ -C₆ alkyl; C₆ -C₁₄ aryl; C₇ -C₁₄ aralkyl andarylcycloalkyl; C₉ -C₁₂ benzocycloalkyl, and C₆ -C₁₄ aryl and aralkylsubstituted with one or more radicals selected from the group consistingof loweralkyl, trifluoromethyl, loweralkoxy, trifluoromethoxy, phenoxy,loweralkylthio, halo, nitro, cyano, C₂ -C₆ alkanoyl, benzoyl,alkoxycarbonyl, diloweralkylamino, loweralkylsulfonyl, fluorosulfonyland alkylsulfinyl; and pharmacologically acceptable addition salts ofthese compounds with acids represented by rHA in which r=0, 1/4, 1/3,1/2, 2/3, 3/4, 1, 5/4, 4/3, 3/2, 5/3, 2, 5/2, 3, 4, 5 and HA is aninorganic or organic acid. Lower alkyl denotes an alkyl group containing1-6 carbon atoms.

The term "carbamylguanidino" includes both unsubstituted andloweralkyl-substituted groups having the formula: ##STR3## wherein R maybe hydrogen or C₁ -C₈ alkyl.

The central group Y may be connected to the substituted guanidino groupB either through the guanidino portion of the group or through thecarbamyl or thiocarbamyl portion. Thus the invention includes compoundsof the following structures: ##STR4## wherein X represents O or S andthe other symbols are as defined above.

The carbamylguanidino compounds of this invention, while retaining thedesirable antimicrobial activity of the bis-biguanide compounds, provideuseful improvements over the latter substances. The carbamylguanidinocompounds of this invention reversibly bind to teeth and oral mucosa toprovide a prolonged intraoral residence time and antimicrobial activity,have an acceptable taste, and are relatively safe to mammals by oraladministration.

A particular deficiency of the bis-biguanide topical antimicrobials suchas chlorhexidine when used to prevent dental plaque formation isstaining of the teeth, tongue, and gums which accompanies theirprolonged used as mouth rinses. A staining mechanism proposed by Nordbo(Nordbo, Scand. J. Dental Res., 79, 356 (1971) postulates a reaction ofchlorhexidine with aldehydes and ketones which are found in the mouth ascomponents of microbial metabolism, and are also present in theglycoprotein constituent of the dental pellicle. The reaction productsare colored and could adhere to the teeth, gums and tongue, forming anunsightly deposit. The ability of chlorhexidine to form such coloredproducts by reaction with aldehydes and ketones is believed to reside inthe biguanide portion of the molecule and particularly in the presenceof the two imino groups of the biguanide radical. The carbamylguanidinecompounds of this invention do not have the two imino groups found inthe biguanide radical. Hence, the compounds of this invention are unableto undergo the color-forming reaction of biguanides such aschlorhexidine with aldehydes and ketones.

The bis-carbamylguanidinoazaalkanes of this invention, by reason of thebasic nitrogen atoms in the Y group, can form acid addition salts havinggreater water-solubility and longer intraoral residence time andantimicrobial activity than the bis-carbamylguanidinoalkanes of U.S.Ser. No. 546,549. The additional water-solubility of these salts is auseful improvement over the art represented by the compound of U.S. Ser.No. 546,549.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the Y portion of the molecule of the compounds of this invention, thechain of atoms may be straight, or branched, or may contain a cyclicstructure.

Suitable Y groups include 3-aza-1,5-pentanediyl,3-methyl-3-aza-1,5-pentanediyl, 3-ethyl-3-aza-1,5-pentanediyl,3-n-propyl-3-aza-1,5-pentanediyl, 3-isopropyl-3-aza-1,5-pentanediyl,3-n-butyl-3-aza-1,5-pentanediyl,3-(1-methylpropyl)-3-aza-1,5-pentanediyl,3-isobutyl-3-aza-1,5-pentanediyl, 3-t-butyl-3-aza-1,5-pentanediyl,3-n-pentyl-3-aza-1,5-pentanediyl,3-(1-methylbutyl)-3-aza-1,5-pentanediyl,3-(2-methylbutyl)-3-aza-1,5-pentanediyl,3-(3-methylbutyl)-3-aza-1,5-pentanediyl,3-(1-ethylpropyl)-3-aza-1,5-pentanediyl,3-n-hexyl-3-aza-1,5-pentanediyl,3-(1-methylpentyl)-3-aza-1,5-pentanediyl, 3-allyl-3-aza-1,5-pentanediyl,3-propargyl-3-aza-1,5-pentanediyl, 3-cyclopentyl-3-aza-1,5-pentanediyl,3-cyclohexyl-3-aza-1,5-pentanediyl, 3-benzyl-3-aza-1,5-pentanediyl,3-aza-1,6-heptanediyl, 4-aza-1,7-heptanediyl,4-methyl-4-aza-1,7-heptanediyl, 4-ethyl-4-aza-1,7-heptanediyl,3-aza-1,7-heptanediyl, 2,4-dimethyl-3-aza-1,5-pentanediyl,2,3,4-trimethyl- 3-aza-1,5-pentanediyl,1,5-dimethyl-3-aza-1,5-pentanediyl,1,3,5-trimethyl-3-aza-1,5-pentanediyl, 5-aza-1,9-nonanediyl,5-methyl-5-aza-1,9-nonanediyl, 1,7-dimethyl-4-aza-1,7-heptanediyl,1,4,7-trimethyl-4-aza-1,7-heptanediyl, 3,6-diaza-1,8-octanediyl,3,6-dimethyl-3,6-diaza-1,8-octanediyl,3,6-diethyl-3,6-diaza-1,8-octanediyl, 4,8-diaza-1,11-undecanediyl,4,8-dimethyl-4,8-diaza-1,11-undecanediyl,2,5,7-trimethyl-3,6-diaza-1,9-nonanediyl,1,4-piperazinediylbis(2,1-ethanediyl),1,4-(1,4-diazacycloheptanediyl)-bis(3,1-propanediyl),1,4-(1,4-diazacyclooctanediyl)bis(2,1-ethanediyl),1,4-piperazinediylbis(3,1-propanediyl),1,4-piperazinediylbis(2-methyl-2,1-ethanediyl),1,4-piperazinediylbis(1-methyl-2,1-ethanediyl),1,4-piperazinediylbis(4,1-butanediyl),cis-2,5-dimethylpiperazinediylbis(3,1-propanediyl),trans-2,5dimethylpiperazinediylbis(3,1propanediyl)1,2-ethanediylbis[4-(1-piperazinyl(2,1-ethanediyl))]and the like.

Among these groups the preferred groups are3-loweralkyl-3-aza-1,5-pentanediyl, 3-loweralkyl-3-aza-1,6-hexanediyl,5-loweralkyl-5-aza-1,7-heptanediyl, 4-loweralkyl-4-aza-1,8-octanediyl,7-loweralkyl-7-aza-1,9-nonanediyl,1,4-piperazinediylbis(loweralkanediyl),1,4-diazacycloheptanediylbis(loweralkanediyl),1,4-diazacyclooctanediylbis(loweralkyanediyl),1,5-diazacyclooctanediyl-bis(loweralkanediyl).1,4-piperazinediylbis(2,1-ethanediyl),1,4-piperazinediylbis-(3,1-propanediyl),1,4-piperazinediylbis(1-methyl-2,1-ethanediyl),1,4-piperazinediylbis(2-methyl-2,1-ethanediyl),1,4-piperazinediylbis(2-methyl-3,1-propanediyl),1,4-(1,4-diazacycloheptanediyl)bis(3,1-propanediyl) and1,4-piperazinediylbis(4,1butanediyl).

Preferred for group B are carbamylguanidino groups, and the preferredcompounds containing these groups are those in which the guanidinoportion of the group is bonded to the central group Y. Thus thepreferred compounds are those having the formula: ##STR5## Suitablegroups for Z in the novel compounds include: C₁ -C₁₂ alkyl, e.g.,methyl, ethyl, 1-propyl, 1-butyl, 1-pentyl, 1-hexyl, 1-heptyl, 1-octyl,1-nonyl, 1-decyl, 1-undecyl, 1-dodecyl, 2-propyl, i-butyl, t-butyl,2-pentyl, i-pentyl, neopentyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 2-ethylbutyl, 1-methylhexyl,2-ethylhexyl, 2-methylheptyl, 1,5-dimethylhexyl, 1,2-dimethylpentyl,1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,1,3,3-tetramethylbutyl; di(C₁-C₁₀)alkylamino-C₁₀ -C₂ alkyl e.g., diethylaminoethyl,2-(N-piperidino)ethyl, 2-(N-morpholino)ethyl; C₃ -C₁₂ alkenyl, e.g.,allyl, 10-undecenyl, 2-ethyl-2-hexenyl, 2,4-dimethyl-2-penten-3-yl,9-decenyl, 5-hexen-3-yl; C₃ -C₁₂ alkynyl, e.g., 2-propynyl, 2-butynyl,2-pentynyl, 2-dodecynyl, 3-butynyl, 4-ethyl-1-hexyn-3-yl; C₃ -C₁₂cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl,1-methylcyclopentyl, 2-methylcyclopentyl, 3-methylcyclopentyl,cyclohexyl, 1-methylcyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl,4-methylcyclohexyl, 2-isopropyl-5-methylcyclohexyl,5-isopropyl-2-methyl-cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cyclododecyl; C₄ -C₁₂ cycloalkylalkyl, e.g.,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl, 1-cyclohexylethyl,2-cyclohexylpropyl, cyclooctylmethyl; C₁ -C₁₀ alkoxy-C₁₀ -C₂ alkyl,e.g., 2-ethoxyethyl, 2-butoxyethyl, 2-hexoxyethyl, 3-hexoxypropyl, C₆-C₁₂ cycloalkenyl, e.g., 2-cyclohexenyl, 3-cyclohexenyl; C₇ -C₁₄cycloalkenylalkyl, e.g., 2-cyclohexenylmethyl, 3-cyclohexenylmethyl,2-(3-cyclohexenyl) ethyl; C₈ -C₁₂ polycycloalkyl, e.g.,cis-hexahydroindan-5-yl, transhexahydroindan-5-yl,1-cis-decahydronaphthyl, 2-cis-decahydronaphthyl1-trans-decahydronaphthyl, 2-trans-decahydronaphthyl, exo-2-norbornyl,endo-2-norbornyl, 1-adamantyl; C₈ -C₁₄ polycycloalkylalkyl, e.g.,1-adamantylmethyl; C₇ -C₁₂ polycycloalkenyl, e.g., bicyclo [2,2.1]hept-5-ene-2-yl; C₈ -C₁₄ polycycloalkenylalkyl, e.g., bicyclo[2.2.2]-oct-5-ene-2-yl-methyl; C₁ -C₁₀ alkylthio-C₁₀ -C₂ alkyl, e.g.,2-ethylthioethyl, 2-butylthioethyl; aryloxy C₂ -C₆ alkyl, e.g.,2-phenoxyethyl, 4-phenoxybutyl; phenylthio C₂ -C₆ alkyl, e.g.,2-phenylthioethyl; C₆ -C₁₄ aryl, e.g. phenyl, 4-biphenyl, 1-naphthyl,5,6,7,8-tetrahydro-1-naphthyl; C.sub. 7 -C₁₄ aralkyl, e.g., benzyl,1-phenylethyl, C₉ -C₁₄ arylcycloalkyl, e.g., 2-phenylcyclopropyl; C₉-C₁₄ benzocycloalkyl, e.g., 1-indanyl, 2-indanyl,1,2,3,4-tetrahydro-1-naphthyl; C₆ -C₁₄ aryl and aralkyl substituted withgroups such as loweralkyl, e.g., 2-tolyl, 3-tolyl, 4-tolyl,2-isopropylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-hexylphenyl,2,4-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl,2,6-diethylphenyl, 2,6-diisopropylphenyl, 2-ethyl-6-methylphenyl,2-methyl-6-isopropylphenyl, 2,4,5-trimethylphenyl,2,4,6-trimethylphenyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl;trifluoromethyl, e.g., 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3,5-bis(trifluoromethyl)phenyl,2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, 2-(3-trifluoromethylphenyl)ethyl; loweralkoxy,e.g., 2-methoxyphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-butoxyphenyl,2,4-dimethoxyphenyl; trifluoromethoxy, e.g., 4-trifluoromethoxyphenyl;phenoxy, e.g., 4-phenoxyphenyl; loweralkylthio, e.g.,3-methylthiophenyl, 4-methylthiophenyl, 4-ethylthiophenyl; halo, e.g.,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 4-iodophenyl, 4-chloro-1-naphthyl, 2,3-dichlorophenyl,2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl,3,4-dichlorophenyl, 2,4-dibromophenyl, 2,5-difluorophenyl,2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2,3,4,5-tetrachlorophenyl,2,3,4,5,6-pentafluorophenyl, 2-chlorobenzyl, 3-chlorobenzyl,4-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 2-(4-chlorophenyl)ethyl,1-(4-chlorophenyl)ethyl; nitro, e.g., 2-nitrophenyl, 3-nitrophenyl,4-nitrophenyl, 4-nitrobenzyl; cyano, e.g., 2-cyanophenyl, 3-cyanophenyl,4-cyanophenyl; alkamoyl, e.g., 2-acetylphenyl, 3-acetylphenyl,4-acetylphenyl, 4-acetylbenzyl; benzoyl, e.g., 4-benzoylphenyl;loweralkoxycarbonyl, e.g., 2-ethoxycarbonyl, 3-ethoxycarbonyl,4-ethoxycarbonyl; diloweralkylamino, e.g., 3-dimethylaminophenyl,4-dimethylaminophenyl, 4-diethylaminophenyl; loweralkylsulfonyl, e.g.,4-butylsulfonylphenyl, 4-methylsulfonylphenyl; fluorosulfonyl, e.g.,3-fluorosulfonylphenyl; loweralkylsulfinyl, e.g.,3-methylsulfinylphenyl, 4-methylsulfinylphenyl; mixed substituents,e.g., 4-bromo-2,6-dimethylphenyl, 2 chloro-6-methylphenyl,5-chloro-2-methylphenyl, 2-chloro-5-trifluoromethylphenyl,4-chloro-3-trifluoromethylphenyl, 2-chloro-3-nitrophenyl,2-chloro-4-nitrophenyl, 2-chloro-5-nitrophenyl, 4-chloro-2-nitrophenyl,2-methoxy-5-methylphenyl, 2-methoxy-4-nitrophenyl,2-methoxy-5-nitrophenyl, 4-methyl-2-nitrophenyl, 4-methyl-3-nitrophenyl,3-chloro-4-fluorophenyl, 3-chloro-2-methoxyphenyl,4-chloro-2-methoxyphenyl, 2-fluoro-3-nitrophenyl,2-fluoro-5-nitrophenyl, 3-chloro-2-phenoxyphenyl,3-chloro-2,4-dimethoxyphenyl, 4,5-dimethyl-2-nitrophenyl,4-methylthio-3-chlorophenyl.

Among these groups the preferred Z groups are C₄ -C₁₂ alkyl, straightchain and branched C₅ -C₁₀ cycloalkyl, C₆ -C₁₀ cycloalkylalkyl, C₆ -C₁₀cycloalkenylalkyl, phenyl, naphthyl, phenyl C₁ -C₄ alkyl, phenyl C₃cycloalkyl, C₁ -C₄ alkylphenyl, C₁ -C₃ alkylbenzyl,trifluoromethylphenyl, trifluoromethylbenzyl,trifluoromethylphenylethyl, C₁ -C₄ alkoxyphenyl, trifluoromethoxyphenyl,phenoxyphenyl, C₁ -C₄ alkylthiophenyl, halophenyl, halobenzyl,halophenylethyl, C₁ -C₄ acylphenyl, C₁ -C₄ alkoxycarbonylphenyl, C₁ -C₄alkylsulfonylphenyl, and trifluoromethylphenylethyl. More preferredgroups are 2-ethylhexyl, 1,5-dimethylhexyl, 1,3-dimethylpentyl,1,4-dimethylpentyl, 1,1,3,3-tetramethylbutyl, 1-methylhexyl,cyclohexylmethyl, cycloheptylmethyl, cyclopentylmethyl,3-cyclohexen-1-ylmethyl, phenyl, 4-tolyl, 1-phenylethyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethoxyphenyl,3-methylthiophenyl, 4-methylthiophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 4 -iodophenyl,4-methylthio-3-chlorophenyl, 1-adamantyl, 2norbornyl, 1-adamantylmethyl,1-(4-chlorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, and2-(3-trifluoromethylphenyl)ethyl.

A preferred genus of Z groups comprises the group consisting of C₄ -C₁₂allkyl, C₅ -C₁₀ cycloalkyl, C₆ -C₁₀ cycloalkylalkyl,3-cyclohexen-1-ylmethyl, C₇ -C₁₀ polycycloalkyl, C₈ -C₁₂polycycloalkylalkyl, phenyl, naphthyl, phenyl C₁ -C₄ alkyl, phenyl C₃cycloalkyl, C₁ -C₄ alkylphenyl, C₁ -C₃ alkylbenzyl,trifluoromethylphenyl, trifluoromethylbenzyl,trifluoromethylphenylethyl, C₁ -C₄ alkoxyphenyl,trifluoromethyoxyphenyl, phenoxyphenyl, C₁ -C₄ alkylthiophenyl,halophenyl, halobenzyl, halophenylethyl, C₂ -C₄ alkanoylphenyl, C₁ -C₄alkoxycarbonylphenyl, and C₁ -C₄ alkylsulfonylphenyl radicals.

By combination of the above described groups, different antimicrobialcompounds can be prepared. The preferred compounds are those exhibitingthe greatest antimicrobial activity, with longest duration of intraoralresidence time and antimicrobial activity. Preferred compounds are thosehaving the formula: ##STR6## wherein Y is selected from the groupconsisting of 3-aza-1,5-pentanediyl, 4-methyl-4-aza-1,8-octanediyl,4-methyl-4-aza-1,7-heptanediyl, 1,4-piperazinediylbis(2,1-ethanediyl),and 1,4-piperazinediyl-(3,1-propanediyl), and Z is selected from thegroup consisting of 2-ethylhexyl, 1,5-dimethylhexyl, 1,3-dimethylhexyl,1,4-dimethylpentyl. 1,1,3,3-tetramethylbutyl, 1-methylhexyl,cyclohexylmethyl, cycloheptylmethyl, cyclopentylmethyl,1-cyclohexylethyl, 2-cyclohexylethyl, 3-cyclohexen-1-ylmethyl, phenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-ethoxyphenyl,3-methylthiophenyl, 4-methylthiophenyl, 3-fluorophenyl, 4-fluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl,3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 4-methylthio-3-chorophenyl,1-adamantyl, 2-norbornyl, 1-adamantylmethyl, 2-(4-chlorophenyl)ethyl,1-(4-chlorophenyl)ethyl, 4-chlorobenzyl.

A preferred genus of compounds is that having the formula ##STR7##wherein Y is selected from the group consisting of3-loweralkyl-3-aza-1,5-pentanediyl, 3-loweralkyl-3-aza-1,6-hexanediyl,5-loweralkyl-5-aza-1,7-heptanediyl, 4-loweralkyl-4-aza-1,8-octanediyl,7-loweralkyl-7-aza-1,9-nonanediyl1,4-piperazinediylbis(loweralkanediyl),1,4-diazacycloheptanediylbis(loweralkanediyl), 1,4-diazacyclooctanediylbis(loweralkyanediyl),1,5-diazacyclooctanediylbis(loweralkanediyl), and Z is selected from thegroup consisting of C₄ -C₁₂ allkyl, C₅ -C₁₀ cycloalkyl, C₆ -C₁₀cycloalkylalkyl, 3-cyclohexen-1-ylmethyl, C₇ -C₁₀ polycycloalkyl, C₈-C₁₂ polycycloalkylalkyl, phenyl, naphthyl, phenyl C₁ -C₄ alkyl, phenylC₃ cycloalkyl, C₁ -C₄ alkylphenyl, C₁ -C₃ alkylbenzyl,trifluoromethylphenyl, trifluoromethylbenzyl,trifluoromethylphenylethyl, C₁ -C₄ alkoxyphenyl, trifluoromethoxyphenyl,phenoxyphenyl, C₁ -C₄ alkylthiophenyl, halophenyl, halobenzyl,halophenylethyl C₂ -C₄ alkanoylphenyl, C₁ -C₄ alkoxycarbonylphenyl andC₁ -C₄ alkylsulfonylphenyl radicals.

Another preferred genus of compounds is that having the formula ##STR8##wherein Y is selected from the group consisting of3-methyl-3-aza-1,5-pentanediyl, 4-methyl-4-aza-1,7-heptanediyl,5-methyl-5-aza-1,9-nonanediyl, 3,6-dimethyl-3,6-diaza-1,8-octanediyl,4,7-dimethyl-4,7-diaza-1,10-decanediyl,1,4-piperazinediylbis(2,1-ethanediyl),1,4-piperazinediylbis(3,1-propanediyl),1,4-piperazinediylbis(1-methyl-2,1-ethanediyl),1,4-piperazinediylbis(2-methyl-2,1-ethanediyl),1,4-piperazinediylbis(2-methyl-3,1-propanediyl),1,4-(1,4-diazacycloheptanediyl) bis(3,1-propanediyl), and Z is selectedfrom the group consisting of 2-ethylhexyl, 1,3-dimethylpentyl,1,4-dimethylpentyl, 1,5-dimethylhexyl, 1,1,3,3-tetramethylbutyl,1-methylhexyl, cyclohexylmethyl, cycloheptylmethyl, cyclopentylmethyl,3-cyclohexen-1-ylmethyl, 1-adamantyl, 2-norbornyl, 1-adamantylmethyl,phenyl, 4-tolyl, 1-phenylethyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-ethoxyphenyl, 3-methylthiophenyl,4-methylthiophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl,3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 4-methylthio-3-chlorophenyl,1-(4-chlorophenyl)-ethyl, 2-(4-chlorophenyl)ethyl, and 2-(3-trifluoromethylphenyl)-ethyl radicals.

It should be understood that the term diloweralkylamino-substitutedphenyl includes both compounds wherein the alkyl groups are separate andcompounds in which the two alkyl groups attached to the amino nitrogenatom are part of a homocyclic or heterocyclic ring.

It is well known in the pharmacological arts that acid addition salts ofpharmacologically active amine compounds do not differ in activitiesfrom their free bases. The salts merely provide a convenient solubilityfactor.

The carbamylguanidino compounds of this invention may be converted totheir pharmaceutically acceptable acid addition salts by customarymethods in the art. The pharmaceutically acceptable salts of thisinvention are those salts, the acid component of which ispharmacologically acceptable in the intended dosages. Suitable salts arethose prepared from inorganic acids or organic acids. Such acidsinclude, but are not limited to: hydrochloric acid, hydrobromic acid,hydrofluoric acid, nitric acid, sulfuric acid, sulfamic acid, thepolyphosphoric acids, phosphoric acid, monofluorophosphoric acid,glycerophosphoric acid, acetic acid, propionic acid, butyric acid,succinic acid, glycolic acid, 2,3-dihydroxypropionic acid, saccharicacid gluconic acid, lactobionic acid, phenylacetic acid,cyclohexylcarboxylic acid, maleic acid, furmaric acid, lactic acid,citric acid, malic acid, camphoric acid, benzoic acid, tartaric acidaspartic acid, salicyclic acid, phthalic acid, methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,nicotinic acid, ascorbic acid and the like. Preferred acids arehydrochloric, acetic, gluconic, and methanesulfonic. Another preferredgenus of acids comprises the group consisting of hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, acetic acid, glycolicacid, 2,3-dihydroxypropionic acid, saccharic acid, gluconic acid,lactobionic acid, maleic acid, fumaric acid, tartaric acid, lactic acid,citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid andascorbic acid.

Compounds containing the carbamylguanidino or thiocarbamylguanidinogroup can be prepared by the general reaction of an organic isocyanateor isothiocyanate with a substituted guanidine according to thefollowing general reaction scheme; ##STR9## wherein R and R' representorganic radicals and X represents oxygen or sulfur.

The procedure for carrying out this reaction is described in Curd, J.Chem. Soc., 1949, 1732-1738.

To prepare a bis-carbamylguanidino compound according to this inventionof the type: ##STR10## one mole of a bis-guanidino compound of theformula: ##STR11## is reacted with two moles of an isocyanate having theformula:

    Z--NCO

by the procedure specified above. The corresponding compound havingsulfur in place of oxygen, i.e., a compound having the formula:##STR12## is prepared analogously by reacting two moles of anisothiocyanate of the formula Z--NCS with one mole of a bis-guanidinocompound. The isothiocyanate can be prepared from the correspondingisocyanate by reaction with O, O'-diethyldithiophosphate according tothe process disclosed in U.S. Pat. No. 3,409,656.

When a compound of the formula: ##STR13## is to be prepared, one mole ofa suitable diisocyanate of the formula

    OCN--Y--NCO

is reacted with two moles of a guanidine of the formula: ##STR14## underthe conditions specified above. Likewise, the analogous compoundcontaining sulfur in place of oxygen, i.e. having the formula: ##STR15##can be prepared by the same procedure using a diisothiocyanate in placeof the diisocyanate.

Since both guanidines and isocyanates can be easily prepared from thecorresponding amino compounds, the novel compounds of this invention maybe synthesized from suitable readily available amines by standardmethods. In one common synthetic procedure, amino groups are convertedto isocyanate groups by reaction with phosgene, COCl₂. A particularsynthesis for the preparation of diisocyanates by this reaction is givenin British Pat. No. 901,337. Other syntheses, such as the thermalrearrangement of azides of carboxylic acids (Curtius rearrangement) andthermal decomposition or base catalyzed decomposition of urethanes,ureas, and the like can also be used to prepare the requiredisocyanates.

The guanidines or bis-guanidines required for synthesizing the compoundsof this invention may be prepared from the corresponding amines by thewell-known reaction with sodium cyanamide or by reaction withS-methylisothiourea sulfate according to the process described in Heyn,U.S. Pat. No. 1,737,192.

Thus the synthesis of compounds of either the formula: ##STR16## 01 orthe formula: ##STR17## from readily available amines and diamines can beillustrated by the following scheme: ##STR18##

A preferred method of synthesizing those compounds wherein Z is analiphatic, alicyclic, or substituted aliphatic or alicyclic groups isthat disclosed in the application by Ronald A. Wohl, filed of even date.In order to synthesize, by that process, compounds having the formula:##STR19## two moles of an S-alkyl isothiobiuret, e.g., a4-methyl-4isothiobiuret having the formula: ##STR20## wherein A is theanion of an acid, are reacted with one mole of a diamine having theformula:

    H.sub.2 N--Y--NH.sub.2

according to the equation: ##STR21## The reaction can be convientlycarried out contacting the reagents in a suitable solvent at atemperature between 20° and 100° C. Suitable solvents inclde alcohols,preferably methanol, water-alcohol mixtures, nitromethane, acetonitrile,and the like. While the above reaction uses the acid addition salt ofthe isothiobiuret, the free base form may also be used. Theisothiobiuret reagent may be prepared by known procedures, e.g., byreacting an isocyanate of the formula:

    Z--N--C═O

with an S-methyl-isothiourea of the formula: ##STR22## according to theequation: ##STR23## This reaction is conveniently carried out by theprocedure described in German Offenlegungsschrift No. 2,326,312,published Dec. 6, 1973. Thus the synthesis of the compounds of thisinvention via the isothiobiuret intermediates, starting from amines andusing well-known reagents and processes may be illustrated by thefollowing scheme: ##STR24##

The reaction of substituted cyanoureas with diamines can also be used toprepare compounds of this invention of the formula: ##STR25## Thus iftwo moles of a substituted cyanourea of the formula: ##STR26## arereacted with one mole of a diamine dihydrochloride of the formula:

    HRN--Y--NHR.2HCl

compounds of the above-described type can be obtained.

It will be understood by the skilled practitioner that when a polyaminehaving two primary amino groups and one or more secondary amino groupsis to be converted into a compound of this invention by the procedureoutlined above, mixtures of compounds may be formed. Hence, it may benecessary to separate the desired bis-guanidines andbis-carbamylguanidines from undesired byproducts formed by reaction ofthe secondary amino groups with the reagent. This separation may beperformed by well-known techniques such as fractional crystallization orchromatography.

Alternatively, the aza groups may be protected from reaction with ZNCOor ZNCS by bonding to them a protective group which can be easilyremoved after the terminal amino groups have been reacted according tothe above scheme. The protective group may be any of those which arecommonly used to temporarily protect secondary amino groups, e.g.,benzyl, acetyl, or carbobenzoxy. The particular protective group chosenmust, of course, be stable toward all reactions used in a particularsynthetic procedure. The protective group may be attached to the azagroups by reacting a precursor of the protective group with a suitablepolyamine after the terminal amine groups have been blocked by reactionwith a blocking group. When the terminal amino groups are primary aminogroups, a phthalimido group, which is specific for blocking primaryamines, may be used under conditions known in the art. After the azagroups have been protected, the terminal amino groups can be regeneratedby removing their blocking groups and the synthesis can be carried outas outlined above. After the synthesis has been completed, the azagroups are regenerated by removing the protective groups by means knownin the art, e.g., by catalytic hydrogenation. The introduction andremoval of protective groups for amines is described in standard texts,e.g., J. F. W. McOmie, Protective Groups in Organic Chemistry, PlenumPress., New York, 1973. Thus the synthesis of a compound of thisinvention by this procedure might proceed as follows: ##STR27##

In an alternative procedure, the polyamine having the aza groupsprotected may be synthesized directly from an amine incorporating theprotective groups. For example, the following reaction sequence may beused. ##STR28## The resulting polyamine may then be used to prepare thecorresponding carbamylguanidine by the reaction scheme outlined above,and the benzyl group may be removed by catalytic hydrogenation to yielda compound according to this invention.

When a compound of the invention having a cyclic diamino skeleton in theY group is desired, the appropriate polyamine starting material can bereacted with a suitable halonitrile or unsaturated nitrile to form aN,N'-bis-alkyl nitrile compound which can subsequently be converted tothe polyamine by catalytic hydrogenation. Thus, the following reactionsequence may be used to prepare a typical cyclic polyamine. ##STR29##

Suitable procedures for preparing polyamines of this type may be foundin Mull, R. P.; Mizzoni, R. H.; Dapero, M. R.; and Egbert, M. E., J.Med. Pharm. Chem., 5, 944-949 (1962) and in Behr, L. C.; Kirby, J. E.:MacDonald, R. N.; and Todd, C. W., J. Am. Chem. Soc., 68, 1296-1297(1946). When polyamines of this type are used as starting materials forpreparing compounds of this invention, no protecting groups need beused, since besides the terminal amino groups which enter into thereaction only tertiary amino groups, which do not carry active hydrogen,are present in the polyamine.

Likewise, when a compound of this invention having an open chain Y groupcontaining only tertiary amino groups within the chain, e.g., --CH₂--CH₂ --N(CH₃)--CH₂ --CH₂ --, is to be prepared, a suitable polyaminehaving terminal primary or secondary amino groups and internal tertiaryamino groups is used as a starting material. Since the tertiary aminogroups are devoid of active hydrogen, they will not react with thereagents used in the general synthesis outlined above. Hence thesynthesis of compounds of the invention of this type is straightforwardand without complication.

The open chain polyamines, terminated with primary or secondary aminogroups, which serve as starting materials for the synthesis of thecompounds of this invention, may be prepared by conventional means. Forexample, amines of the formula ##STR30## Cl--R is an alkyl group may beprepared by condensing two moles of ethyleneimine with a primary aminehaving the formula RNH₂. Similarly, primary amines may be condensed withappropriate halonitriles such as ClCH₂ CN or CL--CH₂ --CH₂ --C═N orCl--CH₂ --CH₂ --CH₂ --CH═N, or acrylonitrile or methacrylonitrile andthe condensation product catalytically hydrogenated to yield polyamineshaving 2 or 3 or 4 carbon atoms between the amino groups. In similarfashion, by means well-known to those skilled in the art, theunsymmetrical polyamines may be prepared. For example, a reaction suchas the following may be employed: ##STR31## wherein Prot is aconventional amine protecting group which is removed after the synthesisis completed.

Amines of the type 1,2-ethanebis[4-(1-(2-aminoethyl)piperazine], havingthe structural formula: ##STR32## may be prepared by reacting1,2-ethanebis(1-piperidine) having the structural formula: ##STR33##(prepared according to the procedures of U.S. Pat. No. 2,943,135) withchloroacetonitrile to form 1,2-ethanebis[4-(1-cyanomethyl) piperazine]having the structural formula: ##STR34## followed by catalytic reductionas outlined above to form the desired amine.

The acid addition salts of the novel compounds are prepared by adding asolution containing an equivalent amount of the corresponding acid to asolution of the compound.

The equivalent amount is determined by the number of ionizable hydrogenatoms present in the acid, and the salt that is desired. The novelcompounds of this invention contain three or more basic sites in themolecule and or all of which may react with the ionizable hydrogen atomsof the acid. Thus, one or more moles of a monobasic acid such ashydrochloric acid, acetic acid, or gluconic acid may react with one moleof the novel compound to form the mono-, tri- or higher saltrespectively. Likewise, one-half mole, one mole or more of a dibasicacid such as sulfuric acid or succinic acid may react with one mole ofthe bis-carbamylguanidine. Again, a tribasic acid such as phosphoricacid or citric acid, may combine in proportions of 1/3, 1/2, 2/3, 1,4/3, 3/2, 5/3, 2 or 3 moles of acid to one mole ofbis-carbamylguanidine, depending on the total number of amino groups inthe molecule. It will be understood by one skilled in the art that theactual salts formed under particular conditions will depend upon theionization constants of the acids and bases and the mole ratio in whichthey are present.

Particularly preferred salts are those containing several anions such asthe trimethanesulfonates and trigluconates of compounds having threebasic groups and the tri- and tetramethanesulfonates and tri- andtetragluconates of compounds having four basic groups.

The antimicrobial activity of the compounds of the invention isdetermined by the following in vitro assays:

A zone of inhibition test is performed by placing a 1/4inch diameterfilter paper disk wet with an aqueous solution of the test compound ofthe chosen concentration on a brain-heart infusion or tripticase soyagar plate seeded with the microorganism to be inhibited. The plate isincubated at 37° C for 24 hours and the diameter of the zone around thefilter paper in which growth of the microorganism has been inhibited ismeasured. The greater the diameter of the zone of inhibition, the moreeffective is the compound against the particular microorganism. Thistest may also be run with the medium diluted with an equal volume ofwater.

A quantitative serial dilution test may also be performed by thefollowing procedure.

A 20 mg/ml solution of the compound to be tested is prepared in astandard brain-heart infusion broth medium which has been diluted withwater to one-half standard strength.

Serial dilutions are prepared by adding 1 ml of the solution to a testtube containing 9 ml of medium. Five milliliters of the resultingsolution are then added to another test tube containing 5 ml of themedium. The resulting solution is then again diluted by the sameprocedure. Ordinarily one tenfold dilution and four twofold dilutionsare made. The procedure can be continued if more dilute solutions arerequired. Each of the series of tubes containing solutions of thecompounds to be assayed is inoculated with two drops of a heavy cultureof the chosen microorganisms in the brain-heart infusion broth. Thetubes are incubated at 37° C for 36 hours and the most dilute solutionshowing no microbial growth is noted. The concentration of this solutionis reported as the minimal inhibitory concentration (MIC).

The compounds of this invention are useful antimicrobials against suchmicroorganisms as S. mutans, A. viscosus, and A. naeslundi, Staph.aureus, E. Coli, Ps. aeruginosa and C. albicans.

Acute oral toxicity of the compounds of the invention is determined inmice by the following procedure. The mice are fasted overnight, thenformed into groups of 10 for testing. The animals in each group are feda chosen dose and the dose is varied from group to group to cover arange of doses. The groups are then observed for a period of five daysand the number of dead animals in each group is noted each day. The LD₅₀is calculated from this data according to the method of Weil,Biometrics, 8(3), 249 263 (1952).

The compounds of this invention show a low order of acute oral toxicity.

The taste of compounds of this invention may be evaluated by standardtaste panels. The compounds of this invention are devoid of theextremely bitter taste associated with chlorhexidine and do not altertaste perception after rinsing the mouth at the concentration useful formicrobial inhibition.

The novel compounds of this invention are useful as topicalantimicrobial agents. Suitable concentrations of these compounds fortopical application to exert their antimicrobial activities are in therange of 0.1% to 5%, preferably 0.5% to 1%.

The antimicrobial compounds of this invention can be administered intothe oral cavity to reduce the numbers of plaque-forming bacteria in themouth. They can be added to toothpastes, tooth powders, mouthwashes, andthe like so as to constitute from 0.1% to 2% of the composition.

A suitable method of treatment is to apply to the teeth once or twice aday a solution having a concentration of 0.1% to 2% preferably 0.2% to1% of a carbamylguanidino compound of this invention. Such a treatmenthas been found to significantly reduce the numbers of plaque-formingbacteria in the mouths of experimental animals.

In in vivo tests the compounds of this invention substantially reducedthe number of S. Mutans in the mouths of hamsters infected with thisorganism for periods up to 6 hours after a single administration.Repeated daily administration further enhances the intraoralantimicrobial activity of these compound.

The invention will be further illustrated by the following exampleswhich are not, however, intended to limit its scope.

EXAMPLE I1,7-bis-(p-chlorophenylcarbamylamidino)-1,4-dimethyl-1,4,7-triazaheptanetrihydrochloride

This example illustrates the synthesis of a compound of this inventionhaving a straight chain nitrogen-containing group.

One gram (0.04 moles) of sodium was dissolved in 100 ml of acetone. Tothis solution was added 6 grams ofN-[2-(1-methylguanidino)ethyl]-N-(2-guanidinoethyl)methylamine sulfateand the mixture was stirred for one hour and 20 minutes. To this mixturewas added 6.2 grams (0.04 moles) of 4-chlorophenylisocyanate. Theresulting mixture was stirred overnight, heated to reflux temperaturefor four hours, cooled, he precipitated sodium sulfate filtered, and thefiltrate concentrated by distilling off the acetone under vacuum, andthen poured into water. An oily material was formed which was separatedfrom the water by decantation, and triturated with diethyl ether. Thesolid was dissolved in 30 milliliters of chloroform, dried overanhydrous sodium sulfate, and hydrogen chloride gas was bubbled throughthe solution until it became acidic. The solvent was removed byevaporation under vacuum, the residue was triturated with anhydrousdiethyl ether, and the trihydrochloride salt of the product collected ona filter. M.P. 220° - 225° C (dec.).

EXAMPLE II 1,4-Bis[2-(4-chlorophenylcarbamylguanidino)propyl]piperazine

This example illustrates the synthesis of a compound of this inventionhaving a heterocyclic ring in the Y radical.

N,N'-Bis-(3-aminopropyl)piperazine (20 g, 0.1 mole) was dissolved inwarm water and added dropwise to a warm aqueous solution of2-methyl-2-thiopseudourea sulfate (27.8 g, 0.1 mole) with stirring. Themixture was stirred for 5 hours and the precipitate which formed wascollected on a filter, washed with cold water, and recrystallized fromwater.

Sodium (1 g, 0.04 mole) was dissolved in acetone with cooling under anitrogen atmosphere. To this solution was addedN,N'-bis-(3-guanidinoproppyl)piperazine sulfate (7.65) g, 0.02 mole) wasadded and the mixture was stirred for two hours. 4-Chlorophenylisocyanate (6.1 g, 0.04 mole) was then added and the mixture was stirredovernight. The mixture was then heated to reflux temperature for onehour, cooled, and the solid precipitate of sodium sulfate removed byfiltration. The solvent was removed from the filtrate and the solidresidue was triturated twice with water. The residue was then trituratedtwice with diethyl ether and collected on a filter. M.P. 199°-202° C(dec.).

The trimethanesulfonate salt was prepared by adding methanesulfonic acid(0.169 ml, 0.00255 mole) and the compound formed above (0.50 g, 0.00085mole) to 50 ml of water and stirring the mixture overnight. The solutionwas filtered to give a clear pale yellow aqueous solution of thetrimethanesulfonate salt.

The dimethanesulfonate salt was prepared by suspending the free base(0.500 g, 0.00085 mole) in ethanol and adding methanesulfonic acid(0.163 g, 0.0017 mole). The mixture was stirred for 1.5 hours. Themixture contained a suspended solid which was collected on a filter andwashed with ethanol. M.P. 195°-198° C.

EXAMPLE III

This example illustrates the synthesis of several carbamylguanidinecompounds of this invention.

When the procedures of Example II are followed using the reagents listedin Table I, the corresponding compounds listed in Table I are prepared.

                                      TABLE I                                     __________________________________________________________________________    Reagents                                                                      Isocyanate     Bis-guanidine    Product                                       __________________________________________________________________________    4-chlorophenyl isocyanate                                                                    1,5-bisguanidino-3-azapentane                                                                  1,5-bis(4-chlorophenylcarbamylguanidino)-                                     8                                                                             3-azapentane                                  4-chlorophenyl isocyanate                                                                    1,5-bisguanidino-3-methyl-3-                                                                   1,5-bis(4-chlorophenylcarbamylguanidino)-                                     .                                                            azapentane       3-methyl-3-azapentane                         4-chlorophenyl isocyanate                                                                    1,5-bisguanidino-3-ethyl-3-                                                                    1,5-bis(4-chlorophenylcarbamylguanidino)-                    azapentane       3-ethyl-3-azapentane                          4-chlorophenyl isocyanate                                                                    1,5-bisguanidino-3-allyl-3-                                                                    1,5-bis(4-chlorophenylcarbamylguanidino)-                    azapentane       3-allyl-3-azapentane                          4-chlorophenyl isocyanate                                                                    1,5-bisguanidino-3-propargyl-3-                                                                1,5-bis(4-chlorophenylcarbamylguanidino)-                    azapentane       3-propargyl-3-azapentane                      4-chlorophenyl isocyanate                                                                    1,5-bisguanidino-3-cyclohexyl-3-                                                               1,5-bis(4-chlorophenylcarbamylguanidino)-                    azapentane       3-cyclohexyl-3-azapentane                     4-chlorophenyl isocyanate                                                                    1,5-bisguanidino-3-benzyl-3-aza-                                                               1,5-bis(4-chlorophenylcarbamylguanidino)-                    pentane          3-benzyl-3-azapentane                         4-chlorophenyl isocyanate                                                                    1,6-bisguanidino-3-azahexane                                                                   1,6-bis(4-chlorophenylcarbamylguanidino)-                                     3-azahexane                                   4-chlorophenyl isocyanate                                                                    1,7-bisguanidino-4-azaheptane                                                                  1,7-bis(4-chlorophenylcarbamylguanidino)-                                     4-azaheptane                                  4-chlorophenyl isocyanate                                                                    1,7-bisguanidino-4-methyl-4-                                                                   1,7-bis(4-chlorophenylcarbamylguanidino)-                    azaheptane       4-methyl-4-azaheptane                         4-chlorophenyl isocyanate                                                                    1,5-bisguanidino-2,3,4-tri-                                                                    1,5-bis(4-chlorophenylcarbamylguanidino)-                    methyl-3-azapentane                                                                            2,3,4-trimethyl-3-azapentane                  4-chlorophenyl isocyanate                                                                    1,9-bisguanidino-5-methyl-5-                                                                   1,9-bis(4-chlorophenylcarbamylguanidino)                     azanonane        5-methyl-5-azanonane                          4-chlorophenyl isocyanate                                                                    1,8-bisguanidino-3,6-diaza-                                                                    1,8-bis(4-chlorophenylcarbamylguanidino)                     octane           3,6-diazaoctane                               4-chlorophenyl isocyanate                                                                    1,8-bisguanidino-3,6-dimethyl-                                                                 1,8-bis(4-chlorophenylcarbamylguanidino)                     3,6-diazaoctane  3,6-dimethyl-3,6-diazaoctane                  4-chlorophenyl isocyanate                                                                    1,11-bisguanidino-4,8-diaza-                                                                   1,11-bis(4-chlorophenylcarbamylguanidino)-                   undecane         4,8-diazaundecane                             4-chlorophenyl isocyanate                                                                    1,11-bisguanidino-4,8-dimethyl-                                                                1,11-bis(4-chlorophenylcarbamylguanidino)-                   4,8-diazaundecane                                                                              4,8-dimethyl-4,8-diazaundecane                4-chlorophenyl isocyanate                                                                    1,11-bisguanidino-3,6,9-triaza-                                                                1,11-bis(4-chlorophenylcarbamylguanidino)-                   undecane         3,6,9-triazaundecane                          4-chlorophenyl isocyanate                                                                    1,4-bis(2-guanidinoethyl)piperazine                                                            1,4-bis[2-(4-chlorophenylcarbamylguanidino                                    )-                                                                            ethyl]piperazine                              4-chlorophenyl isocyanate                                                                    1,4-bis(2-guanidinoethyl)-1,4-                                                                 1,4-bis[2-(4-chlorophenylcarbamylguanidino                                    )-                                                           diazepine        ethyl]-1,4-diazepine                          4-chlorophenyl isocyanate                                                                    1,4-bis(4-guanidinobutyl)piperazine                                                            1,4-bis[4-(4-chlorophenylcarbamylguanidino                                    )-                                                                            butyl]piperazine                              4-bromophenyl isocyanate                                                                     1,5-bisguanidino-3-methyl-3-                                                                   1,5-bis(4-bromophenylcarbamylguanidino)-3-                                    methyl-                                                      azapentane       3-azapentane                                  2-chlorophenyl isocyanate                                                                    1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(2-chlorophenylcarbamylguanidino                                    )-                                                           piperazine       propyl]piperazine                             3-trifluoromethylphenyl-                                                                     1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(3-trifluoromethylphenylcarbamyl                                    -                                             isocyanate     piperazine       guanidino)propyl]piperazine                   phenyl isocyanate                                                                            1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(phenylcarbamylguanidino)propyl]                                    -                                                            piperazine       piperazine                                    4-fluorophenyl isocyanate                                                                    1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(4-fluorophenylcarbamylguanidino                                    )-                                                           piperazine       propyl]piperazine                             4-tolyl isocyanate                                                                           1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(4-tolylcarbamylguanidino)propyl                                    ]-                                                           piperazine       piperazine                                    2,6-diethylphenyl isocyanate                                                                 1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(2,6-diethylphenylcarbamylguanid                                    ino)-                                                        piperazine       propyl]piperazine                             3,4-dichlorophenyl isocyanate                                                                1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(3,4-dichlorophenylcarbamyl-                       piperazine       guanidino)propyl]  piperazine                 4-butoxyphenyl isocyanate                                                                    1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(4-butoxyphenylcarbamylguanidino                                    )-                                                           piperazine       propyl]piperazine                             4-trifluoromethoxyphenyl                                                                     1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(4-trifluoromethoxyphenylcarbamy                                    l-                                            isocyanate     piperazine       guanidino)propyl]piperazine                   4-butylthiophenyl isocyanate                                                                 1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(4-butylthiophenylcarbamylguanid                                    ino)-                                                        piperazine       propyl]piperazine                             4-bromophenyl isocyanate                                                                     1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(4-bromophenylcarbamylguanidino)                                    -                                                            piperazine       propyl]piperazine                             4-butylsuflonylphenyl                                                                        1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(4-butylsulfonylphenylcarbamyl-     isocyanate     piperazine       guanidino)propyl]piperazine                   heptyl isothiocyanate                                                                        1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(heptylthiocarbamylguanidino)-                     piperazine       propyl]piperazine                             benzyl isothiocyanate                                                                        1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(benzylthiocarbamylguanidino)-                     piperazine       propyl]piperazine                             4-chlorophenyl isothiocyanate                                                                1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(4-chlorophenylthiocarbamyl-                       piperazine       guanidino)propyl]piperazine                   3-trifluoromethylphenyl                                                                      1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(3-trifluoromethylphenylthio-       isothiocyanate piperazine       carbamylguanidino)propyl]piperazine           1-naphthyl isocyanate                                                                        1,4-bis(3-guanidinopropyl)-                                                                    1,4-bis[3-(1-naphthylcarbamylguanidino)-                     piperazine       propyl]piperazine                             4-chlorophenyl isocyanate                                                                    1,4-bis(1-methyl-2-guanidinoethyl)-                                                            1,4-bis[2-(4-chlorophenylcarbamylguanidino                                    )-                                                           piperazine       1-methylethyl]piperazine                      4-chlorophenyl isocyanate                                                                    1,4-bis(2-methyl-2-guanidinoethyl)-                                                            1,4-bis[2-(4-chlorophenylcarbamylguanidino                                    -                                                            piperazine       2-methylethyl]piperazine                      4-chlorophenyl isocyanate                                                                    1,4-bis(4-guanidinobutyl)-                                                                     1,4-bis[4-(4-chlorophenylcarbamylguanidino                                    )-                                                           piperazine       butyl]piperazine                              __________________________________________________________________________

EXAMPLE IV 1,4-bis[3-(1-adamantylcarbamylguanidino)propyl]piperazinedihydrochloride.

1.750 grams (5.76 mmole) of 1-(1-adamantyl)-4-methyl-4-isothiobiurethydrochloride and 0.571 g of 1,4-bis(3-aminopropyl)piperazine weredissolved in 5 ml of methanol and allowed to stand at room temperatureovernight. A precipitate formed which was filtered off and washedsuccessively with isopropyl alcohol, isopropyl alcohol-diethyl ethermixture, and diethyl ether. Yield 1.4 g (68%) m.p., 176°-179° C.

EXAMPLE V

This example illustrates the synthesis of other compounds of thisinvention.

Following the procedure of Example IV the compounds listed in Table IIwere prepared by reacting the reagents listed in the table.

                                      TABLE II                                    __________________________________________________________________________    REAGENTS                                                                      ISOTHIOBIURET        DIAMINE          PRODUCT                                 __________________________________________________________________________    1-(n-octyl)-4-methyl-4-isothiobiuret                                                               1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(n-octylcarbamylguanidino)                                          -                                       hydrochloride                         propyl]piperazine dihydrochloride       1-(2-ethylhexyl)-4-methyl-4-isothiobiuret                                                          1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(2-ethylhexylcarbamylguani                                          dino)-                                  hydrochloride                         propyl]piperzine dihydrochloride        1-(1,1,3,3-tetramethylbutyl)-4-methyl-                                                             1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(1,1,3,3-tetramethylbutyl     4-isothiobiuret hydrochloride         carbamylguanidino)propyl]piperazine                                           dihydrochloride                         1,4-dimethyl-4-isothiobiuret                                                                       1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(methylcarbamylguanidino)p                                          ropyl]                                  hydrochloride                         piperazine dihydrochloride              1-dodecyl-4-methyl-4-isothiobiuret                                                                 1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis 3-(dodecylcarbamylguanidino)                                          propyl]                                 hydrochloride                         piperazine dihydrochloride              1-(1,5-dimethylhexyl)-4-methyl-4-isothio-                                                          1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(1,5-dimethylhexylcarbamyl                                          guanidino)                              biuret hydrochloride                  propyl]piperazine dihydrochloride       1-(1,3-dimethylpentyl)-4-methyl-4-isothio-                                                         1,4-bis(3-aminopropyl)-piperazine                                                              1,4-bis[3-(1,3-dimethylpentylcarbamy                                          lguanidino)                             biuret hydrochloride                  propyl]piperazine dihydrochloride       1-(1,4-dimethylpentyl)-4-methyl-4-isothio-                                                         1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(1,4-dimethylpwntylcabamyl                                          guanidino)                              biuret hydrochloride                  propyl]piperazine dihydrochloride       1-(1-methylhexyl)-4-methyl-4-iosthiobiuret                                                         1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(1-methylhexylcarbamylguan                                          idino)propyl]                           hydrochloride                         piperazine dihydrochloride              1-(9-decenyl)-4-methyl-4-isothiobiuret                                                             1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(9-decenylcarbamylguanidin                                          o)propyl]                               hydrochloride                         piperazine dihydrochloride              1-(3-butynyl)-4-methyl-4-isothiobiuret                                                             1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(3-butynylcarbamylguanidin                                          o)propyl]                               hydrochloride                         piperazine dihydrochloride              1-cyclohexyl-4-methyl-4-isothiobiuret                                                              1,4-bis(3-aminopropyl)piperazine                                                               1,4-[3-(cyclohexylcarbamylguanidino)                                          propyl]                                 methanesulfonic acid salt             piperazine dimethanesulfonic acid                                             salt                                    1-cyclohexylmethyl-4-methyl-4-isothiobiuret                                                        1,4-bis(3-aminopropyl)piperazine                                                               1,4-[3-(cyclohexylmethylcarbamylguan                                          idino)propyl]                           hydrochloride                         piperazine dihydrochloride              1-(4-chlorobenzyl)-4-isothiobiuret                                                                 1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(benzylcarbamylguanidino)p                                          ropyl]                                  hydrochloride                         piperazine dihydrochloride              1-[2-(4-chlorophenyl)ethyl]-4-methyl-                                                              1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(2-(4-chlorophenyl)ethylca                                          rbamyl-                                 4-isothiobiuret hydrochloride         guanidino)propyl]piperazine                                                   dihydrochloride                         1-[1-(4-chlorophenyl)ethyl]-4-methyl-4-                                                            1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(1-(4-chlorophenyl)ethylca                                          rbamyl-                                 isothiobiuret hydrochloride           guanidino)propyl]piperazine                                                   dihydrochloride                         1-[2-(4-chlorophenyl-1,1-dimethyl)ethyl]-                                                          1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(2-(4-chlorophenyl-1,1-dim                                          ethyl)ethyl-                            4-methyl-4-isothiobiuret hydrochloride                                                                              carbamylguanidino)propyl]piperazine                                           dihydrochloride                         1-(3-trifluoromethylbenzyl-4-methyl-4-                                                             1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(3-trifluoromethylbenzyl,c                                          arbamyl-                                isothiobiuret hydrochloride           guanidino)propyl]piperazine                                                   dihydrochloride                         1-(3-cyclohexen-1-ylmethyl)-4-methyl-4-                                                            1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(3-cyclohexen-1-ylmethyl)c                                          arbamyl-                                isothiobiuret hydrochloride           guandino)propyl]piperazine                                                    dihydrochloride                         1- (2-norbornyl)-4-methyl-4-isothio-                                                               1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(2-norbornylcarbamylguanid                                          ino)                                    biuret hydrochloride                  propyl]piperazine dihydrochloride       1-(1-adamantyl)-4-methyl-4-isothiobiuret                                                           1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(1-adamantylcarbamylguanid                                          ino)                                    methanesulfonic acid salt             propyl]piperazine dimethanesulfonic                                           acid salt                               1-(1-adamantylmethyl)-4-methyl-4-isothio-                                                          1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(1-adamantylmethylcarbamyl                                          guanidino)                              biuret hydrochloride                  propyl]piperazine dihydrochloride       1(1,2,3,4-tetrahydro-1-naphthyl)-4-methyl-                                                         1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-((1,2,3,4-tetrahydro-1-nap                                          hthyl)                                  4-isothiobiuret hydrochloride         carbamylguanidino)propyl]piperazine                                           dihydro-                                                                      chloride                                1-(4-chlorophenyl)-4-methyl-4-isothio-                                                             1,4-bis(3-aminopropyl)piperazine                                                               1,4-[3-(4-chlorophenylcarbamylguanid                                          ino)propyl]                             biuret hydrochloride                  piperazine dihydrochloride              1-benzyl-4-methyl-4-isothiobiuret                                                                  1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(benzylcarbamylguanidino)p                                          ropyl]                                  hydrochloride                         piperazine dihydrochloride              2-indanyl-4-methyl-4-isothiobiuret                                                                 1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(2-indanylcarbamylguanidin                                          o)propyl]                               hydrochloride                         piperazine dihydrochloride              1-cyclohexylmethyl-4-methyl-4-isothiobiuret                                                        N,N-bis(3-aminopropyl)methylamine                                                              1,7-bis(cyclohexylmethylcarbamylguan                                          idino)-3-                               hydrochloride                         methyl-3-azaheptane                                                           trihydrochloride                        1-cyclohexylmethyl-4-methyl-4-isothiobiuret                                                        1,4-bis(2-aminoethyl)piperazine                                                                1,4-bis[2-(cyclohexylmethylcarbamylg                                          uanidino)                               hydrochloride                         ethyl]piperazine dihydrochloride        1-cyclohexylmethyl-4-methyl-4-isothiobiuret                                                        1,4-bis(3-aminopropyl),1,4-diaza-                                                              1,4-bis[3-(cyclohexylmethylcarbamylg                                          uanidino)                               hydrochloride        cycloheptane     propyl]-1,4-diazacycloheptane                                                 dihydrochloride                         1-cyclohexylmethyl-4-methyl-4-iso-2,4-                                                             N,N-bis(2-aminoethyl)methylamine                                                               1,5-bis(cyclohexylmethylthiocarbamyl                                          guanidino)-4-                           dithipbiuret hydrochloride            methyl-4-azapentane                                                           trihydrochloride                        1-cyclohexylmethyl-4-methyl-4-isothio-                                                             1,4-bis(2-aminoethyl)piperazine                                                                1,4-bis[2-(cyclohexylmethylcarbamylg                                          uanidino)                               biuret methanesulfonic acid salt      ethyl]piperazine dimethanesulfonic                                            acid salt                               1-cyclohexylmethyl-4-methyl-4-isothio-                                                             bis(3-aminopropyl)methylamine                                                                  1,7-bis[(cyclohexylmethyl)carbamylgu                                          anidino]-                               biuret hydrochloride                  4-methyl-4-azaheptane                                                         dihydrochloride                         1-cyclohexylmethyl-4-methyl-4-isothio-                                                             5,8-dimethyl-2,5,8,11-                                                                         1,10-bis[(cyclohexylmethyl)carbamyla                                          midino]-                                biuret hydrochloride tetraazadodecane 1,4,7,10-tetramethyl-1,4,7,10-tetraa                                          zadecane                                                                      dihydrochloride                         1-(1-adamantyl)-4-methyl-4-isothio-                                                                1,4-bis(2-aminoethyl)piperazine                                                                1,4-bis[2-((1-adamantyl)carbamylguan                                          idino)                                  biuret methanesulfonic acid salt      ethyl]piperazine dimethanesulfonic                                            acid salt                               1-(1-adamantyl)-4-methyl-4-isothio-                                                                1,4-bis(4-aminobutyl)piperazine                                                                1,4-bis[4-(1-adamantyl)carbamylguani                                          dino)                                   biuret methanesulfonic acid salt      butyl]piperazine dimethanesulfonic                                            acid salt                               1-(1-adamantyl)-4-methyl-4-isothio-                                                                1,4-bis(2-aminopropyl)piperazine                                                               1,4-bis[4-(2-((1-adamantyl)carbamylg                                          uanidino)                               biuret methanesulfonic acid salt      propyl]piperazine dimethanesulfonic                                           acid salt                               1-t-butyl-4-methyl-4-isothiobiuret                                                                 1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(t-butylcarbamylguanidino)                                          propyl]                                 methanesulfonic acid salt             piperazine dimethanesulfonic acid                                             salt                                    1-cycloheptyl-4-methyl-4-isothiobiuret                                                             1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(cycloheptylcarbamylguanid                                          ino)                                    methanesulfonic acid salt             propyl]piperazine dimethanesulfonic                                           acid salt                               1-n-hexyl-4-methyl-4-isothiobiuret                                                                 1,4-bis(3-aminopropyl)piperazine                                                               1,4-bis[3-(n-hexylcarbamylguanidino)                                          propyl]                                 methanesulfonic acid salt             piperazine dimethanesulfonic acid                                             salt                                    1-(1-cyclohexylethyl)-4-methyl-isothio-                                                            1,4-bis(2-aminoethyl)piperazine                                                                1,4-bis[2-((1-cyclohexylethyl)carbam                                          ylguanidino)                            biuret methanesulfonic acid salt      ethyl]piperazine dimethanesulfonic                                            acid salt                               1-tert-octyl-4-methyl-4-isothiobiuret                                                              1,4-bis(2-aminoethyl)piperazine                                                                1,4-bis[2-(tert-octylcarbamylguanidi                                          no)ethyl]                               methanesulfonic acid salt             piperazine dimethanesulfonic acid                                             salt                                    __________________________________________________________________________

EXAMPLE VI

This example shows the antimicrobial effectiveness of the compounds ofthis invention in vitro.

The minimum inhibitory concentration of a number of a number ofcompounds of this invention with respect to the microorganism S. Mutans,Strain OMZ-176E were determined by the procedure described above. Theresults are tabulated in Table III. Chlorhexidine diacetate, acommercially successful antimicrobial, was used as a control.

                                      TABLE III                                   __________________________________________________________________________                                             MIC                                  COMPOUND                                 γ/ml                           __________________________________________________________________________    1,7-bis(4-chlorophenylcarbamylguanidine)-4-methyl-4-azaheptane                                                         0.625                                1,4-bis[3-(4-chlorophenylcarbamylguanidino)propyl]piperazine                                                           0.156 - 0.312                        1,8-bis(4-chlorophenylcarbamylguanidino)-3,6-dimethyl-3,6-diazaoctane                                                  1.25                                 1,4-bis[3-(1-adamantylcarbamylguanidino)propyl]piperazine                                                              0.625rochloride                      1,4-bis[(3-cyclohexylmethylcarbamylguanidino)propyl]piperazine                dihydrochloride                          1.25                                 1,4-bis[3-(1,1,3,3-tetramethylbutylcarbamylguanidino)propyl]piperazine        dihydrochloride                          1.25                                 1,4-bis[3-(n-octylcarbamylguanidino)propyl]piperazine dihydrochloride                                                  2.50                                 1,4-bis[3-(2-ethylhexylcarbamylguanidino)propyl]piperazine                    dihydrochloride                          5.0                                  1,4-bis[3-(2-(4-chlorophenyl)ethylcarbamylguanidino)propyl]piperazine         dihydrochloride                          1.25                                 chlorhexidine diacetate                  0.156 - 0.312                        __________________________________________________________________________

EXAMPLE VII

A number of compounds of this invention were tested for in vitroantimicrobial activity against several pathogenic microorganisms usingthe above described procedure except that trypticase soy broth was usedin place of half strength brain-heart infusion as the medium. Theresults, which are given in Table IV, show that the compounds of thisinvention have antimicrobial activity against the common pathogens E.coli, S. aureus, C. albicans, A. niger, and Ps. aeruginosa.

                                      TABLE IV                                    __________________________________________________________________________    MINIMUM INHIBITORY CONCN. MCG/ML                                              Compound           E. coli                                                                           S. aureus                                                                          Ps. aeruginosa                                                                       C. albicans                                                                         A. niger                             __________________________________________________________________________    1,4-bis[3-(cyclohexylmethylcarbamyl-                                                             6.25                                                                              0.78 100    6.25  12.5                                 guanidino)propyl]piperazine                                                   dimethanesulfonic acid salt                                                   1,4-bis[3-((1-adamantyl)carbamyl-                                                                25. 6.25 50     12.5  12.5                                 guanidino)propyl]piperazine                                                   dimethanesulfonic acid salt                                                   1,4-bis[3-(cyclohexylcarbamylguanidino)                                                          100.                                                                              50.  100    50.   100.                                 propyl]piperazine dimethanesulfonic                                           acid salt                                                                     1,4-bis[3-(cycloheptylmethyl-                                                                    12.5                                                                              0.78 12.5   0.78  50.                                  carbamylguanidino)propyl]piperazine                                           dimethanesulfonic acid salt                                                   1,4-bis[2-((1-adamantyl)carbamyl-                                                                12.5                                                                              0.39 6.25   0.78  50.                                  guanidino)ethyl]piperazine                                                    dimethanesulfonic acid salt                                                   1,4-bis[3-(1-methylhexyl)carbamyl-                                                               12.5                                                                              1.56 25     6.25  25.                                  guanidino)propyl]piperazine                                                   dihydrochloride                                                               Chlorhexidine      1.56                                                                              0.39 50     3.12  12.5                                 __________________________________________________________________________

EXAMPLE VIII

The staining properties of the compound of Example II were compared withthose of chlorhexidine by the following procedure.

Test solutions were prepared containing 0.2% and 1% of chlorhexidine and0.2% and 1% of the compound of Example II as the trimethanesulfonatesalt.

Extracted human incisors, which were used without cleaning or othertreatment which would remove the dental pellicle, were suspended fromwires. Daily, each tooth was immersed for 10 minutes in one of the testsolutions, then suspended in whole stimulated saliva and incubated at37° C for 24 hours.

After ten days of exposure of the teeth to the test solutions, agreyish-brown discoloration was noted only on the teeth exposed tochlorhexidine. The amount of discoloration appeared to be independent ofthe concentration of this agent. The teeth exposed to the compound ofExample II showed no signs of discoloration.

I claim:
 1. A compound having the formula ##STR35## wherein Y is anitrogen-containing alkylene group having the structural formula##STR36## wherein: n = 2-4m = 2-4 p = 2 q = 2 y = 1-2R' and R" are eachhydrogen or C₁ -C₄ alkyl and may be the same or different; and Z isselected from the group consisting of C₁ -C₁₂ alkyl; di(C₁ -C₁₀alkylamino)-C₁₀ -C₂ alkyl, (1-piperidino)alkyl and (1-morpholino)alkylhaving a total carbon content of C₄ -C₁₂ ; C₃ -C₁₂ alkenyl; C₃ -C₁₂alkynyl, C₃ -C₁₂ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, C₆ -C₁₂cycloalkenyl, C₇ -C₁₄ cycloalkenylalkyl, C₇ -C₁₂ polycycloalkyl, C₈ -C₁₄polycycloalkylalkyl, C₇ -C₁₂ polycycloalkenyl, C₈ -C₁₄polycycloalkenylalkyl, C₁ -C₁₀ alkoxy-C₁₀ -C₂ alkyl having a totalcarbon content of C₃ -C₁₄ ; C₁ -C₁₀ alkylthio-C₁₀ -C₂ alkyl having atotal carbon content of C₃ -C₁₄ ; phenoxy C₂ -C₆ alkyl; phenylthio C₂-C₆ alkyl; C₆ -C₁₄ aryl; C₇ -C₁₄ aralkyl and C₉ -C₁₄ arylcycloalkyl; C₉-C₁₂ benzocycloalkyl, and C₆ -C₁₄ aryl and aralkyl substituted with oneor more radicals selected from the group consisting of lower alkyl,trifluoromethyl, loweralkoxy, trifluoromethoxy, phenoxy, loweralkylthio,halo, nitro, cyano, C₂ -C₆ alkanoyl, benzoyl, loweralkoxycarbonyl,diloweralkylamino, loweralkylsulfonyl, fluorosulfonyl andloweralkylsulfinyl; and pharmacologically acceptable addition salts ofthese compounds with acids.
 2. A compound according to claim 1 wherein Zis selected from the group consisting of C₄ -C₁₂ alkyl, C₅ -C₁₀cycloalkyl, C₆ -C₁₀ cycloalkylalkyl, 3-cyclohexen-1-ylmethyl, C₇ -C₁₀polycycloalkyl, C₈ -C₁₂ polycycloalkylalkyl, phenyl, naphthyl, phenyl C₁-C₄ alkyl, phenyl C₃ cycloalkyl, C₁ -C₄ alkylphenyl, C₁ -C₃ alkylbenzyl,trifluoromethylphenyl, trifluoromethylbenzyl,trifluoromethylphenylethyl, C₁ -C₄ alkoxyphenyl,trifluoromethyoxyphenyl, phenoxyphenyl, C₁ -C₄ alkylthiophenyl,halophenyl, halobenzyl, halophenylethyl, C₂ -C₄ alkanoylphenyl, C₁ -C₄alkoxycarbonylphenyl, and C₁ -C₄ alkylsulfonylphenyl radicals.
 3. Acompound according to claim 1 wherein Y is1,4-piperazinediylbis(loweralkanediyl), and Z is selected from the groupconsisting of C₄ -C₁₂ alkyl, C₅ -C₁₀ cycloalkyl, C₆ -C₁₀cycloalkylalkyl, 3-cyclohexen-1-ylmethyl, C₇ -C₁₀ polycycloalkyl, C₈-C₁₂ polycycloalkylalkyl, phenyl, naphthyl, phenyl C₁ -C₄ alkyl, phenylC₃ cycloalkyl, C₁ -C₄ alkylphenyl, C₁ -C₃ alkylbenzyl,trifluoromethylphenyl, trifluoromethylbenzyl,trifluoromethylphenylethyl, C₁ -C₄ alkoxyphenyl, trifluoromethoxyphenyl,phenoxyphenyl, C₁ -C₄ alkylthiophenyl, halophenyl, halobenzyl,halophenylethyl, C₂ -C₄ alkanoylphenyl, C₁ -C₄ alkoxycarbonylphenyl andC₁ -C₄ alkylsulfonylphenyl radicals.
 4. A compound according to claim 3wherein Y is selected from the group consisting of1,4-piperazinediylbis(2,1-ethanediyl),1,4-piperazinediylbis(3,1-propanediyl),1,4-piperazinediylbis-(1-methyl-2,1-ethanediyl),1,4-piperazinediylbis(2-methyl-2,1-ethanediyl),1,4-piperazinediylbis(2-methyl-3,1-propanediyl), and Z is selected fromthe group consisting of 2-ethylhexyl, 1,3-dimethylpentyl,1,4-dimethylpentyl, 1,5-dimethylhexyl, 1,1,3,3-tetramethylbutyl,1-methylhexyl, cyclohexylmethyl, cycloheptylmethyl, cyclopentylmethyl,3-cyclohexen-1-ylmethyl, 1-adamantyl, 2-norbornyl, 1-adamantylmethyl,phenyl, 4-tolyl, 1-phenylethyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-ethoxyphenyl, 3-methylthiophenyl,4-methylthiophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl,3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 4-methylthio-3-chlorophenyl,1-(4-chlorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, and2-(3-trifluoromethylphenyl)ethyl radicals.
 5. A compound according toclaim 3 wherein Z is halophenyl.
 6. A compound according to claim 3wherein Z is trifluoromethylphenyl.
 7. A compound according to claim 3wherein Z is adamantyl.
 8. A compound according to claim 3 wherein Z iscyclohexylmethyl.
 9. A compound according to claim 1 having the formula##STR37## .rHA wherein r = 1/4, 1/3, 1/2, 2/3, 3/4, 1, 5/4, 4/3, 3/2, 2,5/3, 3, 4, 5 and HA is an inorganic or organic acid.
 10. A compoundaccording to claim 9 wherein said acid, HA, is selected from the groupconsisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, acetic acid, glycolic acid, 2,3-dihydroxypropionic acid, saccharicacid, gluconic acid, lactobionic acid, maleic acid, furmaric acid,tartaric acid, lactic acid, citric acid, malic acid, methanesulfonicacid, ethanesulfonic acid and ascorbic acid. 11.1,4-bis[3-(4-chlorophenylcarbamylguanidino)propyl]-piperazine orpharmacologically acceptable acid addition salts. 12.1,4-bis[3-(1-adamantylcarbamylguanidino)propyl]piperazine orpharmacologically acceptable acid addition salts. 13.1,4-bis[3-(cyclohexylmethylcarbamylguanidino)propyl]piperazine orpharmacologically acceptable acid addition salts. 14.1,4-bis[3-(1,1,3,3-tetramethylbutylcarbamylguanidino)propyl]-piperazineor pharmacologically acceptable acid addition salts. 15.1,4-bis[3-(n-octyl carbamylguanidino)propyl]piperazine orpharmacologically acceptable acid addition salts. 16.1,4-bis[3-(4-chlorophenylethylcarbamylguanidino)propyl]-piperazine orpharmacologically acceptable acid addition salts. 17.1,4-bis[3-(2-ethylhexylcarbamylguanidino)propyl]piperazine orpharmacologically acceptable acid addition salts. 18.1,4-bis[2-(1-adamantylcarbamylguanidino)-1-methylethyl]-piperazine orpharmacologically acceptable acid addition salts. 19.1,4-bis[2-(1-adamantylcarbamylguanidino-2-methylethyl]-piperazine orpharmacologically acceptable acid addition salts. 20.1,4-bis[4-(1-adamantylcarbamylguanidino)butyl]piperazine orpharmacologically acceptable acid addition salts. 21.1,4-bis[2-(1-methylhexylcarbamylguanidino)ethyl]piperazine orpharmacologically acceptable acid addition salts. 22.1,4-bis[2-((1-adamantylmethyl)carbamylguanidino)ethyl]piperazine orpharmacologically acceptable acid addition salts. 23.1,4-bis[2-((1-adamantyl)carbamylguanidino)ethyl]-trans-2,5-dimethylpiperazineor pharmacologically acceptable acid addition salts. 24.1,4-bis[2-((1-adamantyl)carbamylguanidino)ethyl]-piperazine orpharmacologically acceptable acid addition salts. 25.1,4-bis[2-((2-indanyl)carbamylguanidino)ethyl]piperazine orpharmacologically acceptable acid addition salts.
 26. A compoundaccording to claim 3 wherein Z is 1-hexyl.